Method for administering insulin to the buccal region

ABSTRACT

A mixed micellar pharmaceutical formulation includes a micellar pharmaceutical agent, an alkali metal C8 to C22 alkyl sulfate, alkali metal salicylate, a pharmaceutically acceptable edetate and at least one absorption enhancing compound. The absorption enhancing compounds are selected from the group consisting of lecithin, hyaluronic acid, pharmaceutically acceptable salts of hyaluronic acid, octylphenoxypolyethoxyethanol, glycolic acid, lactic acid, chamomile extract, cucumber extract, oleic acid, linolenic acid, borage oil, evening primrose oil, trihydroxy oxo cholanyiglycine, glycerin, polyglycerin, lysine, polylysine, triolein and mixtures thereof. Each absorption enhancing compound is present in a concentration of from 1 to 10 wt:/wt. % of the total formulation, and the total concentration of absorption enhancing compounds are less than 50 wt./wt. % of the formulation. Methods for administering insulin and heparin to the buccal region are also disclosed.

RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.10/378,371, filed Mar. 3, 2003, which is a continuation of U.S.application Ser. No. 09/538,829, filed Mar. 30, 2000, now U.S. Pat. No.7,070,799, issued Jul. 4, 2006, which is a continuation-in-part of U.S.application Ser. No. 09/216,733, filed Dec. 21, 1998, now U.S. Pat. No.6,231,882, issued May 15, 2001, which is a continuation-in-part of U.S.application Ser. No. 09/021,114, filed Feb. 10, 1998, now U.S. Pat. No.6,017,545, issued Jan. 25, 2000. The entire teachings of the aboveapplications are incorporated herein by reference.

FIELD OF THE INVENTION

The present invention relates to an improved delivery system for theadministration of large-molecule pharmaceuticals, e.g. peptidic drugs,vaccines and hormones. In particular it relates to pharmaceuticals whichmay be administered through the oral and nasal membranes.

BACKGROUND OF THE INVENTION

In spite of significant efforts in academic and commercial laboratories,major breakthroughs in oral peptide and protein formulation have notbeen achieved. Relatively little progress has been made in reaching thetarget of safe and effective oral formulations for peptides andproteins. The major barriers to developing oral formulations forproteins and peptides include poor intrinsic permeability, lumenal andcellular enzymatic degradation, rapid clearance, and chemical stabilityin the gastrointestinal (GI) tract. Pharmaceutical approaches to addressthese barriers, which have been successful with traditional small,organic drug molecules, have not readily translated into effectivepeptide and protein formulations. Although the challenges aresignificant, the potential therapeutic benefits remain high especiallyin the field of diabetes treatment using insulin.

Scientists have explored various administration routes other thaninjection for proteins and peptides. These routes include oral,intranasal, rectal, and vaginal cavities for the effective delivery oflarge molecules. Out of the above four mentioned routes, oral and nasalcavities have been of greatest interest to scientists. Both the oral andnasal membranes offer advantages over other routes of administration.For example, drugs administered through these membranes have a rapidonset of action, provide therapeutic plasma levels, avoid first passeffect of hepatic metabolism, and avoid exposure of the drug to thehostile GI environment. Additional advantages include easy access to themembrane sites so that the drug can be applied, localized and removedeasily. Further, there is a good potential for prolonged delivery oflarge molecules through these membranes.

The oral routes have received far more attention than have the otherroutes. The sublingual mucosa includes the membrane of ventral surfaceof the tongue and the floor of the mouth whereas the buccal mucosaconstitutes the lining of the cheek. The sublingual mucosa is relativelypermeable thus giving rapid absorption and acceptable bioavailability ofmany drugs. Further, the sublingual mucosa is convenient, acceptable andeasily accessible. This route has been investigated clinically for thedelivery of a substantial number of drugs.

The ability of molecules to permeate through the oral mucosa appears tobe related to molecular size, lipid solubility and peptide proteinionization. Small molecules, less than 1.000 daltons, appear to crossmucosa rapidly. As molecular size increases, the permeability decreasesrapidly. Lipid soluble compounds are more permeable than non-lipidsoluble, molecules. Maximum absorption occurs when molecules areun-ionized or neutral in electrical charges. Therefore charged moleculespresent the biggest challenges to absorption through the oral mucosae.

Most proteinic drug molecules are extremely large molecules withmolecular weights exceeding 6000 daltons. These large molecules havevery poor lipid solubility and are practically impermeable. Substancesthat facilitate the absorption or transport of large molecules (>2000daltons) across biological membranes are known as enhancers, (Lee etal., Critical Reviews in Therapeutic drug Carrier Systems, 8, 91, 1991;Lee et al., Critical Reviews in Therapeutic drug Carrier Systems, 8,115, 1991, 1992). Enhancers may be characterized as chelators, bilesalts, fatty acids, synthetic hydrophilic and hydrophobic compounds, andbiodegradable polymeric compounds.

Various mechanisms of action of enhancers have been proposed. Thesemechanisms of action, at least for protein and peptidic drugs include(1) reducing viscosity and/or elasticity of mucous layer, (2)facilitating transcellular transport by increasing the fluidity of thelipid bilayer of membranes, and (3) increasing the thermodynamicactivity of drugs (Critical Rev, 117-125, 1991, 1992).

Many enhancers have been tested so far and some have been found to beeffective in facilitating mucosal administration of large moleculedrugs. However, hardly any penetration enhancing products have reachedthe market place. Reasons for this include lack of a satisfactory safetyprofile respecting irritation, lowering of the barrier function, andimpairment of the mucociliary clearance protective mechanism. The mainfactor to be considered in the use of enhancers, especially thoserelated to bile salts, and some protein solubilizing agents, isextremely bitter and unpleasant taste. This makes their use almostimpossible for human consumption on a daily basis. Several approacheswere utilized to improve the taste of the bile salts based deliverysystems, but none one of them are commercially acceptable for humanconsumption to date. Approaches utilized include patches for buccalmucosa, bilayer tablets, controlled release tablets, use of proteaseinhibitors, buccally administered film patch devices, and variouspolymer matrices.

The basic problem associated with the above technologies is the use oflarge quantities of bile acids and their salts to promote the transportof the large molecules through membranes in the form of localizeddelivery systems using patches or tablets. In spite of using proteaseinhibitors and polymer coatings the technologies failed to deliverproteinic drugs in the required therapeutic concentrations. Further, theproblem is compounded because of the localized site effect of the patchwhich resulted in severe tissue damage in the mouth. Most attempts weremade to deliver large molecules via the oral, nasal, rectal, and vaginalroutes using single bile acids or enhancing agents in combination withprotease inhibitors and biodegradable polymeric materials. However, itis extremely difficult to achieve therapeutic levels of proteinic drugsusing these formulations, as single enhancing agents fail to loosentight cellular junctions in the oral, nasal, rectal and vaginal cavitiesfor a required period of time to allow passage of large moleculesthrough the mucosal membranes without further degradation. This problemmakes it impractical to use the above mentioned systems for a commercialpurpose.

In order to overcome the above mentioned problem of the bitter taste,irritation and the penetration of large molecules through thesublingual, buccal and GI tract mucosal lining, a system has now beendesigned where a proteinic drug was encapsulated in mixed micelles madeup of a combination of enhancers, e.g. yolk proteins (lecithins). Thissystem allows the opening of the paracellular junctions (tightjunctions) in the oral cavity as well as in the GI tract by GI motilitymovement with a high degree of protease activity preserved and forprotecting molecules from premature degradation in the hostile acidicand proteolytic GI environment.

It is believed that the mixed micelles encapsulate molecules with highdegree of efficiency (>90% encapsulation). These mixed micelles areextremely small in size (1 nm to 10 nm), and are smaller than the poresof the membranes in the oral cavity or the GI tract. It is thereforebelieved that the extremely small size of mixed micelles helpsencapsulated molecules penetrate efficiently through the mucosalmembranes of the oral cavity.

The absorption of proteins and peptides is believed to be enhanced bythe diffusion of large molecules entrapped in the mixed micellar formthrough the aqueous pores and the cell structure perturbation of thetight paracellular junctions.

The amount of physiologically active peptide or protein in thecompositions of this invention is typically a quantity that provides aneffective amount of the drug to produce the physiological activity(therapeutic plasma level) for which the peptide or protein is beingadministered. In consideration of the fact that the bioavailability ofany active substance can never be 100%, that is to say the administereddose of the active drug is not completely absorbed, it is preferable toincorporate a slightly larger amount than the desired dosage. Where thedosage form is a spray (aerosol) or the like which is repeatedlydispensed from the same container, it is recommendably so arranged thatthe unit dose will be slightly greater than the desired dose. It shouldbe understood that dosage should vary with species of warm bloodedanimals such as man, domestic animals, and their body weights. Thecomposition of this invention is prepared as microfine droplets (1 to 10nm or less) by virtue of the preparation methods used and suitablecombinations of enhancer compound characteristics. The utilization ofatomizer or aerosol spray devices (metered dose inhalers or nebulizers)may be useful to further reduce the particle size for effectiveinhalation from the nasal or oral cavity so that the drug may besuccessfully be absorbed or reach to the specific site.

The therapeutic composition of the present invention can be stored atroom temperature or at cold temperatures. Storage of proteinic drugs ispreferable at cold temperatures to prevent the degradation of the drugsand to extend their shelf life. While the mixed micellar therapeuticcomposition of the invention is applied to the mucosal membranes, thesites of administration may be the same as those used for usual mucosaltherapeutic preparations. Generally, oral, transdermal and nasal are thefavorite sites of administration but the composition can be applied tothe rectal and vaginal mucosa. According to the physiologically activepeptide or protein used, the dosage form and the site of administration,a specific administration method can be selected.

As used herein, the term “edetate” refers to pharmaceutically acceptablesalts of ethylenediaminetetraacetic acid.

It is known that improvements in penetration and absorption of mixedmicellar formulations can be achieved by mixing the mixed micellarformulation with propellants such as tetrafluoroethane,heptafluoroethane, dimethylfluoropropane, tetrafluoropropane, butane,isobutane, dimethyl ether and other non-CFC and CFC propellants,Preferably they are delivered through metered dose spray devices.Metered dose inhalers are known and are a popular pulmonary drugdelivery form for some drugs. The present formulation, including thepropellant, is intended to improve the quality of absorption, stabilityand performance of many formulations. The propellants, as will beappreciated by those skilled in the art, give enhancement in thepenetration through pores, and facilitate absorption of the drugs toreach therapeutic levels in the plasma. The present formulation may beabsorbed buccally, by ensuring that the person does not inhale theformulation as it is sprayed. One of the other benefits of using anatomizer or inhaler is that the potential for contamination is minimizedbecause the devices are self contained.

SUMMARY OF THE INVENTION

Accordingly the present invention provides a mixed micellarpharmaceutical formulation, having a pH of between 6.0 and 7.0comprising a pharmaceutical agent in micellar form, water, an alkalimetal lauryl sulphate in a concentration of from 1 to 10 wt./wt. % ofthe total formulation, a pharmaceutically acceptable edetate in aconcentration of from 1 to 10 wt./wt. % of the total formulation, atleast one alkali metal salicylate in a concentration of from 1 to 10wt./wt. % of the total formulation, and at least one micelle formingcompound selected from the group consisting of lecithin, hyaluronicacid, pharmaceutically acceptable salts of hyaluronic acid,octylphenoxypolyethoxyethanol, glycolic acid, lactic acid, chamomileextract, cucumber extract, oleic acid, linolenic acid, borage oil,evening primrose oil, trihydroxy oxo cholanyiglycine, glycerin,polyglycerin, lysine, polylysine, triolein and mixtures thereof, whereineach absorption enhancing compound is present in a concentration of from1 to 10 wt./wt. % of the total formulation, and the total concentrationof absorption enhancing compounds is less than 50 wt./wt. % of theformulation.

In an embodiment, the alkali metal lauryl sulphate, the edetate and thealkali metal salicylate are each in a concentration of from 2 to 5wt./wt. % of the total formulation.

In one embodiment, the edetate is an alkali metal edetate. Preferablythe alkali metal edetate be selected from the group consisting ofdisodium edetate, dipotassium edetate, and combinations thereof.

In another embodiment, the alkali metal lauryl sulphate is sodium laurylsulphate.

In a further embodiment, the alkali metal salicylate is sodiumsalicylate.

In another embodiment, the lecithin is selected from the groupconsisting of saturated phospholipid, e.g. Phospholipon-H (trade mark)saturated phospholipid, unsaturated phospholipid, e.g. Phospholipon-G(trade mark) unsaturated phospholipid, phosphatidylcholine, phosphatidylserine, sphingomyelin, phosphatidylethanolamine, cephalin, andlysolecithin.

In one embodiment, one of the absorption enhancing compounds is selectedfrom the group consisting of hyaluronic acid, pharmaceuticallyacceptable salts of hyaluronic acid and mixtures thereof, theconcentration of such micelle forming compound being from about 1 toabout 5 wt./wt. %.

In another embodiment, suitable for delivery through nasal passages, themixed micellar pharmaceutical formulation is suitably diluted to avoidirritation of the nasal passages.

Another aspect of the present invention provides a mixed micellarpharmaceutical formulation, comprising a pharmaceutical agent inmicellar form, water, an alkali metal C8 to C22 alkyl sulphate in aconcentration of from 1 to 10 wt./wt. % of the total formulation, apharmaceutically acceptable edetate in a concentration of from 1 to 10wt./wt. % of the total formulation, at least one alkali metal salicylatein a concentration of from 1 to 10 wt./wt. % of the total formulation,and at least one micelle forming compound selected from the groupconsisting of lecithin, hyaluronic acid, pharmaceutically acceptablesalts of hyaluronic acid, octylphenoxypolyethoxyethanol, glycolic acid,lactic acid, chamomile extract, cucumber extract, oleic acid, linolenicacid, borage oil, evening primrose oil, menthol, trihydroxy oxocholanylglycine and pharmaceutically acceptable salts thereof, glycerin,polyglycerin, lysine, polylysine, polidocanol alkyl ethers and analoguesthereof, triolein and mixtures thereof, wherein each absorptionenhancing compound is present in a concentration of from 1 to 10 wt./wt.% of the total formulation, and the total concentration of absorptionenhancing compounds is less than 50 wt./wt. % of the formulation.

Yet another aspect of the present invention provides that the mixedmicellar aerosol pharmaceutical formulation additionally comprises aphenolic compound selected from the group consisting of phenol andmethyl phenol in a concentration of from 1 to 10 wt./wt. % of the totalformulation, and a propellant known for use with aerosol pharmaceuticalformulations such as propellants selected from the group consisting ofC1-C2 dialkyl ether, butanes, fluorocarbon propellant,hydrogen-containing fluorocarbon propellant, chlorofluorocarbonpropellant, hydrogen-containing chlorofluorocarbon propellant, andmixtures thereof.

In one embodiment, the alkali metal C8 to C22 alkyl sulphate is in aconcentration of from 2 to 5 wt./wt. % of the total formulation.

In another embodiment, the alkali metal C8 to C22 alkyl sulphate issodium lauryl sulphate.

In another embodiment, the lecithin is saturated or unsaturated,preferably selected from the group consisting of phosphatidylcholine,phosphatidyl serine, sphingomyelin, phosphatidylethanolamine, cephalin,and lysolecithin.

In yet another embodiment, one of the micelle forming compounds isselected from the group consisting of hyaluronic acid, pharmaceuticallyacceptable salts of hyaluronic acid, polidocanol alkyl ethers,trihydroxy oxo cholanyl glycine, polyoxyethylene ethers and mixturesthereof, the concentration of such absorption enhancing compound beingfrom about 1 to about 5 wt./wt. %.

Preferably, the ratio of pharmaceutical agent, e.g. insulin, topropellant is in a ratio practiced in the art, such as from 5:95 to25:75.

In another embodiment, the propellant known for use with aerosolpharmaceutical formulations, such as propellants selected from the groupconsisting of tetrafluoroethane, tetrafluoropropane,dimethylfluoropropane, heptafluoropropane, dimethyl ether, n-butane and25 isobutane.

In yet another embodiment, the mixed micellar pharmaceutical formulationis contained in an aerosol dispenser, known in the pharmaceutical artsfor aerosol administration of drugs.

For insulin-containing and some other compositions, the composition mayalso contain at least one inorganic salt which opens channels in thegastrointestinal tract and may provide additional stimulation to releaseinsulin. Non-limiting examples of inorganic salts are sodium, potassium,calcium and zinc salts, especially sodium chloride, potassium chloride,calcium chloride, zinc chloride and sodium bicarbonate.

It will be recognized by those skilled in the art that for manypharmaceutical compositions it is usual to add at least one antioxidantto prevent degradation and oxidation of the pharmaceutically activeingredients. It will also be understood by those skilled in the art thatcolorants, flavoring agents and non-therapeutic amounts of othercompounds may be included in the formulation. Typical flavoring agentsare menthol and sorbitol.

In one embodiment the antioxidant is selected from the group consistingof tocopherol, deteroxime mesylate, methyl paraben, ethyl paraben andascorbic acid and mixtures thereof. A preferred antioxidant istocopherol.

In a preferred embodiment at least one protease inhibitor is added tothe formulation to inhibit degradation of the pharmaceutical agent bythe action of proteolytic enzymes. Of the known protease inhibitors,most are effective at concentrations of from 1 to 3 wt./wt. % of theformulation.

Non-limiting examples of effective protease inhibitors are bacitracin,soyabean trypsin, aprotinin and bacitracin derivatives, e.g. bacitracinmethylene disalicylate. Bacitracin is the most effective of those namedwhen used in concentrations of from 1.5 to 2 wt./wt. %. Soyabean trypsinand aprotinin may be used in concentrations of about 1 to 2 wt./wt. % ofthe formulation.

The formulation suitable for delivery through oral mucosal membranes maybe in chewable form, in which case it will be necessary to addingredients suitable for such form. Such ingredients include guar gum,powdered acacia, carrageenan, beeswax and xanthan gum.

The pharmaceutical agent may be selected from a wide variety ofmacromolecular agents, depending on the disorder being treated,generally with molecular weights greater than about 1000 and especiallybetween about 1000 and 2 000 000. Preferred pharmaceutical agents areselected from the group consisting of insulin, heparin, low molecularweight heparin, hirulog, hirugen, huridin, interferons, interleukins,cytokines, mono and polyclonal antibodies, immunoglobins,chemotherapeutic agents, vaccines, glycoproteins, bacterial toxoids,hormones, calcitonins, insulin like growth factors (IGF), glucagon likepeptides (GLP-1), large molecule antibiotics, protein based thrombolyticcompounds, platelet inhibitors, DNA, RNA, gene therapeutics andantisense oligonucleotides, and small molecule drugs, e.g. opioids,narcotics, analgesics, NSAIDS, steroids, hypnotics, pain killers,morphine and the like.

The present invention also provides a process for making apharmaceutical composition suitable for delivery through transdermalmembranes comprising: a) preparing a pharmaceutical agent composition inmicellar form in an aqueous medium which has an alkali metal salicylatein a concentration of from 1 to 10 wt./wt. % of the aqueous micellarpharmaceutical agent composition, an alkali metal lauryl sulphate in aconcentration of from 1 to 10 wt./wt. % of the aqueous micellarpharmaceutical agent composition and a pharmaceutically acceptableedetate in a concentration of from 1 to 10 wt./wt. % of the aqueousmicellar pharmaceutical agent composition; b) slowly adding the micellarpharmaceutical agent composition to at least one of the absorptionenhancing compounds selected from the group consisting 10 of lecithin,hyaluronic acid, pharmaceutically acceptable salts of hyaluronic acid,octylphenoxypolyethoxyethanol, glycolic acid, lactic acid, chamomileextract, cucumber extract, oleic acid, linolenic acid, borage oil,evening primrose oil, 15 trihydroxy oxo cholanylglycine, glycerin,polyglycerin, lysine, polylysine, triolein and mixtures, thereof, whilemixing vigorously, to form a mixed micellar composition; wherein eachabsorption enhancing compound is each present in a concentration of from1 to 10 wt./wt. % of the total formulation, and the total concentrationof alkali metal salicylate, alkali metal lauryl sulphate, edetate andabsorption enhancing compounds is less than 50 wt./wt. % of theformulation.

In one embodiment, the process provides an additional step of adding,while continuing vigorous mixing, at least one absorption enhancingcompound different from that added in step b), selected-from the groupconsisting of lecithin, hyaluronic acid, pharmaceutically acceptablesalts of hyaluronic acid, octylphenoxypolyethoxyethanol, glycolic acid,lactic acid, chamomile extract, cucumber extract, oleic acid, linolenicacid, borage oil, evening primrose oil, trihydroxy oxo cholanylglycine,glycerin, polyglycerin, lysine, polylysine, triolein and mixturesthereof.

In one embodiment the alkali metal lauryl sulphate is sodium laurylsulphate.

In another embodiment the alkali metal salicylate is sodium salicylate.

In a further embodiment the alkali metal edetate may be selected fromthe group consisting of disodium edetate and dipotassium edetate.

In yet another embodiment, the formulation has a combination selectedfrom the group consisting of i) sodium hyaluronate and unsaturatedphospholipid, ii) Phospholipon-H and glycolic acid, and iii) sodiumhyaluronate and lecithin.

The present invention also provides a process for making apharmaceutical composition suitable for delivery by means of an aerosolcomprising: a) preparing a pharmaceutical agent composition in micellarform in an aqueous medium which has an alkali metal C8 to C22 alkylsulphate in a concentration of from 1 to 10 wt./wt. % of the aqueousmicellar pharmaceutical agent composition, a pharmaceutically acceptableedetate in a concentration of from 1 to 10 wt./wt. % of the aqueousmicellar pharmaceutical agent composition, at least one alkali metalsalicylate in a concentration of from 1 to 10 wt./wt. % of the aqueousmicellar pharmaceutical agent composition; b) slowly adding the micellarpharmaceutical agent composition to at least one of the absorptionenhancing compounds selected from the group consisting of lecithin,hyaluronic acid, pharmaceutically acceptable salts of hyaluronic acid,octylphenoxypolyethoxyethanol, glycolic acid, lactic acid, chamomileextract, cucumber extract, oleic acid, linolenic acid, borage oil,evening primrose oil, menthol, trihydroxy oxo cholanylglycine andpharmaceutically acceptable salts thereof, glycerin, polyglycerin,lysine, polylysine, polidocanol alkyl ethers and analogues thereof,triolein and mixtures thereof, while mixing vigorously, to form a mixedmicellar composition; and optionally c) an additional step of adding,while continuing vigorous mixing, at least one micelle forming compounddifferent from that added in step b), selected from the group consistingof lecithin, hyaluronic acid, pharmaceutically acceptable salts ofhyaluronic acid, glycolic acid, lactic acid, chamomile extract, cucumberextract, oleic acid, linoleic acid, linolenic acid, monoolein, borageoil, evening primrose oil, glycerin, polyglycerin, lysine, polylysine,triolein, polyoxyethylene ethers and analogues thereof, polidocanolalkyl ethers and analogues thereof, and mixtures thereof; d) mixing themixed micellar composition resulting from steps a) to e) with a phenoliccompound selected from the group consisting of phenol, m-cresol andmixtures thereof; and subsequently e) placing the formulation into anaerosol dispenser known in the pharmaceutical arts for aerosoladministration of drugs and charging the dispenser with a propellantknown for use with such aerosol dispensers; wherein each of theabsorption enhancing compound is present in a concentration of from 1 to10 wt./wt. % of the total formulation, and the total concentration ofalkali metal salicylate, alkali metal C8 to C22 alkyl sulphate, edetateand absorption enhancing compounds is less than 50 wt./wt. % of theformulation.

The vigorous mixing may be accomplished using high speed stirrers, e.g.magnetic stirrers or propellor stirrers, or by sonication.

In one embodiment, the mixed micellar formulation is formed bysonication of the aqueous micellar pharmaceutical agent composition inthe presence of lecithin.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

The present invention provides an improved method for delivery ofmacromolecular (high molecular weight) pharmaceutical agents,particularly through the membranes in the nose, mouth, vagina or rectum.The preferred delivery is through oral and nasal cavities. Thepharmaceutical agents cover a wide spectrum of agents, includingproteins, peptides, hormones, vaccines and drugs. The molecular weightsof the macromolecular pharmaceutical agents are preferably above 1000,especially between 1000 and 2 000 000.

For example, hormones which may be administered with the presentinvention include thyroids, androgens, estrogens, prostaglandins,somatotropins, gonadotropins, erythropoetin, interferons, interleukins,steroids and cytokines. Vaccines which may be administered with thepresent invention include bacterial and viral vaccines such as vaccinesfor hepatitis, influenza, tuberculosis, canary pox, chicken pox,measles, mumps, rubella, pneumonia, BCG, HIV and AIDS. Bacterial toxoidswhich may be administered using the present invention includediphtheria, tetanus, pseudomonas and mycobacterium tuberculosis.Examples of specific cardiovascular or thrombolytic agents includeheparin, hirugen, hirulos and hirudin. Large molecules usefullyadministered with the present invention include monoclonal antibodies,polyclonal antibodies and immunoglobins.

As will be understood, the concentration of the pharmaceutical agent isan amount sufficient to be effective in treating or preventing adisorder or to regulate a physiological condition in an animal or human.The concentration or amount of pharmaceutical agent administered willdepend on the parameters determined for the agent and the method ofadministration, e.g. oral, nasal. For example, nasal formulations tendto require much lower concentrations of some ingredients in order toavoid irritation or burning of the nasal passages. It is sometimesdesirable to dilute an oral formulation up to 10-100 times in order toprovide a suitable nasal formulation.

The mixed micellar formulation is prepared by first preparing a firstmicellar composition which contains the pharmaceutically active agents,alkali metal C8 to C22 alkyl sulphate, edetate and alkali metalsalicylate. For those compositions intended for administration throughthe nasal, oral, vaginal or rectal cavities, the first micellarcomposition is then added to at least one of the absorption enhancingcompounds to form a mixed micellar composition. At least one otherabsorption enhancing compound may also be added subsequently. Preferablythe first absorption enhancing compound is lecithin.

When making the aerosol formulation, the phenol and/or m-cresol and/orisotonic agent are then added. The formulation is then put into anaerosol dispenser and the dispenser charged with the propellant in amanner known in the art.

The preferred propellants in the art are hydrogen-containingchlorofluorocarbons, hydrogen-containing fluorocarbons, dimethyl etherand diethyl ether. Even more preferred is hydrofluoroalkane (HFA) 134a(1,1,1,2 tetrafluoroethane).

Although the present invention has such wide applicability, theinvention is described hereinafter with particular reference to insulinand its analogues, which are used for the treatment of diabetes.

As indicated hereinbefore, the compositions of the present inventionrequire that the pharmaceutical formulation be in mixed micellar form.

In the case of insulin, which is intended for administration throughnasal or oral cavities, the first micellar solution may be made byadding a buffer solution to powdered insulin, and then stirring untilthe powder is dissolved and a clear solution is obtained. A typicalbuffer solution is an aqueous solution of sodium salicylate and sodiumlauryl sulphate and disodium edetate. Typical concentrations of sodiumsalicylate and sodium lauryl sulphate in the aqueous solution are about3 to 20 wt./wt. % of each compound in the solution. Typically, insulinis present in the micellar solution in an amount which will give aconcentration of about 2 to 4 wt./wt. % of the final formulation.Typically the concentration may be about 10 wt./wt. % of the firstmicellar composition.

The micellar solution is then added slowly to the first absorptionenhancing compound, e.g. lecithin while mixing vigorously, e.g.sonicating, to form a mixed micellar solution. At least one otherabsorption enhancing compound selected from the group consisting oflecithin, hyaluronic acid, pharmaceutically acceptable salts ofhyaluronic acid, octylphenoxypolyethoxyethanol, glycolic acid, lacticacid, chamomile extract, cucumber extract, oleic acid, linolenic acid,borage oil, evening primrose oil, trihydroxy oxo cholanylglycine,glycerin, polyglycerin, lysine, polylysine, triolein is then added. Themixing may be done with a high speed mixer or sonicator to ensureuniform micelle particle size distribution within the formulation.

Each of the absorption enhancing compounds, when present, is in aconcentration of from 1 to 10 wt./wt. % of the total formulation.

Preferred salts of hyaluronic acid are alkali metal hyaluronates,alkaline earth hyaluronates and aluminium hyaluronate. The preferredsalt is sodium hyaluronate. The preferred concentration of hyaluronicacid or pharmaceutically acceptable salts of hyaluronic acid is from 1to 5 wt./wt. % of the total formulation. An even more preferred range isfrom 1.5 to 3.5 wt./wt. % of the total formulation.

Other ingredients may be added to the mixed micellar solution. Forexample, flavouring agents, antioxidants, salts, protease inhibitors orother pharmaceutically acceptable compounds may be added.

In general the size of the micelle particles in the solution is about 1to 10 nm, and preferably from 1 to 5 nm. Such a size distributionensures effective absorption of the formulation, and therefore thepharmaceutical agent, through the membranes, for example the membranesin the oral and nasal cavities.

The specific concentrations of the essential ingredients can bedetermined by relatively straightforward experimentation. For absorptionthrough the nasal and oral cavities, it is often desirable to increase,e.g. double or triple, the dosage which is normally required throughinjection or administration through the gastrointestinal tract.

As will be understood, the amount of each component of the formulationwill vary depending on the pharmaceutical agent and the site ofapplication. Preferred formulations for oral or nasal application havethe following combinations: i) sodium lauryl sulphate, sodiumsalicylate, disodium edetate, Phospholipon-H and sodium hyaluronate; ii)sodium lauryl sulphate, sodium salicylate, disodium edetate, lecithinand sodium hyaluronate; iii) sodium lauryl sulphate, sodium salicylate,disodium edetate, sodium hyaluronate and evening primrose oil; iv)sodium lauryl sulphate, sodium salicylate, disodium edetate,Phospholipon-H and bacitracin; v) sodium lauryl sulphate, sodiumsalicylate, disodium edetate, Phospholipon-H, sodium hyaluronate andbacitracin; and vi) sodium lauryl sulphate, sodium salicylate, disodiumedetate, sodium hyaluronate, oleic acid and gamma linoleic acid.

For aerosol formulations, the addition of a mixture of phenol andm-cresol is preferred. Such an aerosol formulation may then be chargedto an aerosol dispenser and then charged with a propellant in a mannerknown in the art, preferably a non-CFC propellant.

The therapeutic compositions of the present invention may be stored atroom temperature or at cold temperature. Storage of proteinic drugs ispreferable at a cold temperature to prevent degradation of the 10 drugsand to extend their shelf life.

As indicated hereinbefore, generally, oral and nasal are the favouriteroutes of administration but the composition can be applied to therectal and vaginal mucosa. According to the physiologically activepeptide or protein used, the dosage form and the site of administration,a specific administration method can be selected.

The composition of this invention is generally prepared as microfinemixed micellar particles (1 to 10 20 nm or less) by virtue of thepreparation methods used and suitable combinations of absorptionenhancer characteristics.

For oral and nasal application, sprays are preferable, but drops,chewable tablets, chewable gum and other suitable forms may be used.Utilization of atomizer or aerosol spray devices (metered dose inhalersor nebulizers) can be used to further reduce the particle size foreffective inhalation from the nasal or oral cavity so the drug maysuccessfully reach to the specific site and be absorbed. It is alsopossible to utilize a drug delivery system such that an enteric coatingis applied to the gelatin capsule to cause the micelles to be releasedonly in the duodenum or in the proximity of the large intestine and notin the stomach.

The invention is illustrated by reference to the following examples.

Example 1

A first experiment was conducted to provide data for comparativepurposes. This example does not fall within the scope of the presentinvention.

A solution was prepared using 0.5 g sodium lauryl sulphate, 0.5 g sodiumsalicylate and 0.25 g disodium edetate dissolved in 10 mL of water. Tothis solution 40 mg (1000 units) of insulin was added and dissolvedcompletely while stirring, to give about 100 units/mL insulin solution.

In one set of tests, five healthy non-diabetic human volunteers weretested with insulin, by injection. In another set of tests thevolunteers were tested with insulin, taken orally. The volunteers fastedfrom midnight prior to the test, with no food being taken during the 4hour study.

On the first day, the volunteers received 10 units of insulin byinjection (regular fast acting insulin, available from Eli Lilly). Onthe second day, the volunteers received 100 units (1 mL volume per drop,approximately 20 drops) of the above-prepared oral insulin (10 times theinjection dose). In both tests, blood glucose levels were monitoredevery 15 minutes by Bayer's Glucometer Elite.

The average results for the five volunteers, of the first day's trial(sub-cutaneous injection with 10 units) were as follows:

TABLE I Time* 0 15 30 60 75 90 120 150 180 210 240 Avg: 5.8 5.8 5.4 5.04.6 4.3 3.8 3.6 3.4 4.2 4.5 *time in minutes

The results for each of the five volunteers, of the second day's trial(oral drops with 100 units) were as follows:

TABLE II Subject Time*: Nos: 0 15 30 60 75 90 120 150 180 210 240 1 6.25.8 5.2 5.0 4.9 5.0 5.0 4.8 4.7 5.5 6.0 2 5.8 5.4 5.0 4.7 4.9 4.3 5.05.5 5.2 5.8 6.1 3 4.8 4.6 4.3 4.3 4.4 4.6 4.8 4.7 5.2 5.5 5.1 4 6.6 6.15.8 5.5 5.1 4.9 5.0 5.0 5.9 6.2 6.8 5 6.0 5.8 5.7 5.5 5.1 4.8 4.7 4.95.0 5.9 6.7 *time in minutes

These tests indicate that compared to the injection method, oral insulingives a faster onset of action and lowers blood glucose levels withoutcreating a hypoglycaemic condition. Due to the hepatic glucoseproduction, there was a rebound effect. This is believed to be due tothe incomplete absorption of insulin.

Example 2

Another experiment, not within the scope of the present invention, wasperformed for comparative purposes.

Oral insulin (100 units) was formulated in (Phospholipon-H, 10 mg)without any sodium lauryl sulphate, sodium salicylate, edetate orabsorption enhancers, to evaluate its efficacy of blood glucose loweringin a fasted state, for healthy volunteers.

Volunteers were asked to fast overnight and not have any breakfast priorto dosing. Volunteers were asked to take this oral insulin formulationin their mouth and swallow it. Blood glucose levels were monitored every15 minutes using Bayer's glucometer Elite for 3 hours, and the averageresults for 5 volunteers are shown in Table III.

TABLE III Time*: 0 15 30 45 60 75 90 120 150 180 Avg: 5.6 5.8 5.8 5.75.7 5.8 5.7 5.7 5.8 5.7 *time in minutes

This indicates that orally administered insulin with lecithin alone hasno effect on blood glucose lowering.

Example 3

A further experiment, not within the scope of the present invention, wasperformed for comparative purposes.

Oral insulin (100 units) was formulated with sodium salicylate andalkali metal edetate (both 5% by wt.) to evaluate its efficacy of bloodglucose lowering in fasted state in healthy volunteers.

Volunteers were asked to fast overnight and not have any breakfast priorto dosing. Volunteers were asked to take this oral insulin formulationin their mouth and swallow it. Blood glucose levels were monitored every15 minutes using Bayer's glucometer Elite—for 3 hours and the averageresults for 10 volunteers are shown in Table IV.

TABLE IV Time*: 0 15 30 45 60 75 90 120 150 180 Avg: 5.8 5.8 5.8 5.9 5.85.9 5.7 5.9 6.2 6.0 *time in minutes

This indicates that orally administered insulin with sodium salicylateand alkali metal edetate alone has no effect on blood glucose lowering.In addition, this formulation caused irritation and burning sensation,which lasted for several hours.

Example 4

A further experiment, not within the scope of the present invention, wasperformed for comparative purposes.

Oral insulin (100 units) was formulated using sodium salicylate andalkali metal edetate (both 5% by wt.) with Phospholipon-H (10 mg) andtested on healthy subjects. Blood glucose levels were monitored every 15minutes using Bayer's glucometer Elite for 3 hours and the results areshown in Table V.

TABLE V Time*: 0 15 30 45 60 90 120 180 Avg: 5.3 5.3 5.3 5.4 5.6 5.7 5.75.8 *time in minutes

This indicates that orally administered insulin with sodium salicylate,alkali metal edetate and Phospholipon-H has no effect on blood glucoselowering.

Example 5

Another experiment, not within the scope of the present invention, wasperformed for comparative purposes.

Oral insulin (50 units) was formulated using only alkali metal laurylsulphate (5% by wt). Blood glucose levels were monitored every 15minutes using Bayer's glucometer. Elite for 3 hours and the averageresults for four volunteers are shown in Table VI.

TABLE VI Time*: 0 15 30 60 90 20 180 Avg: 5.8 5.6 5.4 5.3 5.4 5.4 5.6*time in minutes

This data shows that orally administered insulin with only alkali metallauryl sulphate has little metabolic effect on the blood glucoselowering in healthy subjects. This formulation caused substantialburning sensation and irritation in the subjects and lasted for twodays.

Example 6

Yet another experiment, within the scope of the present invention, wasperformed.

Mixed micellar oral insulin (50 units) was formulated using alkali metallauryl sulphate and sodium salicylate (both 4.4% by wt,) and alkalimetal edetate (2.2% by wt) with Phospholipon-H (10 mg) and tested onhealthy volunteers.

The method involved mixing the sodium lauryl sulphate, sodium salicylateand alkali metal edetate with water in a beaker with a magnetic stirrerat medium speed until the ingredients were dissolved, to form buffersolution. Insulin powder was placed in a beaker and to this powder wasadded the buffer solution. The solution was continuously stirred using amagnetic stir bar until all of the insulin powder was dissolved and aclear solution obtained. The micellar solution so formed was stored inclean glass bottles and refrigerated.

Mixed micellar insulin was then prepared in a glass beaker, in which wasplaced the Phospholipon H and a small amount of isopropyl alcohol. Themixture was stirred at a high speed (1000 rpm) for about 10 minutes toensure complete dissolution of the Phospholipon-H. To this solution wasadded the micellar insulin solution very slowly, drop wise, using glassdropper, with continuous stirring at a high speed. The solution wasstirred continuously for another 30 minutes at a high speed to ensureuniform micellar particle size distribution.

Samples of the mixed micellar solution were taken 25 orally by thevolunteers.

Blood glucose levels were monitored every 15 minutes using Bayer'sglucometer Elite for 3 hours and the average results for 5 volunteersare shown in Table VII.

TABLE VII Time: 0 15 30 45 60 90 120 150 180 Avg: 6.5 6.1 5.5 5.3 5.35.4 5.5 5.5 5.5 * time in minutes

This data shows that orally administered insulin with alkali metallauryl sulphate combined with the sodium salicylate and alkali metaledetate with Phospholipon-H has a small metabolic effect on bloodglucose levels in healthy volunteers.

Example 7

An experiment, within the scope of the present invention, was performed.In this example, the formulation was for oral administration.

Oral insulin (50 units) was formulated using alkali metal laurylsulphate and sodium salicylate (both 4.4% by wt.) and alkali metaledetate (2.2% by wt.) with Phospholipon-H (10 mg) and sodium hyaluronate(1.1% by wtj. This formulation was tested on healthy subjects underfasting condition.

The method involved mixing the sodium lauryl sulphate, sodium salicylateand alkali metal edetate with water in a beaker with a magnetic stirrerat medium speed until the ingredients were dissolved, to form buffersolution. Insulin powder was placed in a beaker and to this powder wasadded the buffer solution. The solution was continuously stirred using amagnetic stir bar until all of the insulin powder was dissolved and aclear solution obtained. The micellar solution so formed was stored inclean glass bottles and refrigerated.

Mixed micellar insulin was then prepared In a glass beaker, in which wasplaced the Phospholipon-H and a small amount of isopropyl alcohol. Themixture was stirred at a high speed (1000 rpm) for about 10 minutes toensure complete dissolution of the Phospholipon-H. To this solution wasadded the micellar insulin solution very slowly, drop wise, using glassdropper, with continuous stirring at a high speed. The solution wasstirred continuously for another 30 minutes at a high speed to ensureuniform micellar particle size distribution. The hyaluronate and smallamounts of menthol and sorbitol were then added, with continuousstirring.

Samples of the mixed micellar solution were taken orally by thevolunteers.

Blood glucose levels were monitored every 15 minutes using Bayer'sglucometer Elite for 3 hours and the average results for 5 volunteersare shown in Table VIII.

TABLE VIII Time:* 0 15 30 45 60 90 120 150 180 Avg: 6.5 5.9 5.6 5.4 4.95.0 4.9 5.2 5.4 *time in minutes

This data shows that orally administered insulin with alkali metallauryl sulphate, sodium salicylate, alkali metal edetate, Phospholipon-Hand sodium hyaluronate has resulted in lowering of blood glucose levelsin healthy subjects better than the above mentioned formulations.

Example 8

A further experiment, within the scope of the present invention, wasperformed. In this example, the formulation was for oral administration.

A buffer solution was prepared using 0.5 g sodium lauryl sulphate, 0.5 gsodium salicylate and 0.25 g disodium edetate dissolved in 10 mL ofwater. The solution was added to insulin and mixed, to form micellarinsulin.

Separately, 100 mg of powdered Phosphatidylcholine-H was added to aglass beaker and to this powder was added 10 mL 50% ethanol. The powderwas dissolved completely. To this solution 16 mg (400 units) of micellarinsulin solution dissolved in 3 mL of the buffer solution to (give 30units/mL insulin solution) was added slowly with vigorous mixing, toform a mixed micellar solution. To this was added 0.6 mL of sodiumhyaluronate and 0.2 ml of 2% menthol solution containing 3% sorbitol.

In one set of tests, ten Type II diabetic human volunteers who tookinsulin, by injection three times a day, were studied. In another set oftests the volunteers were tested with insulin, faken orally. Thevolunteers fasted from midnight prior to the test, with no food beingtaken during the 4 hour study.

On the first day, the volunteers received 10 units insulin by injection(regular fast acting insulin, available from Eli Lilly). On the secondday, the volunteers received 30 units (1 mL volume per drop,approximately 20 drops) of the above-prepared oral insulin (3 times theinjection dose). In both tests, blood glucose levels were monitoredevery 15 minutes by Bayer's Glucometer Elite.

The results, showing the average for the ten volunteers, were as shownon the following page:

TABLE IX Blood glucose levels (mmol/L) Time (minutes) Oral Dose (30units) Injection (10 units) 0 6.4 6.8 15 5.8 6.9 30 5.4 6.1 45 5.3 5.860 5.3 5.8 75 5.2 5.8 90 5.2 5.4 105 5.2 5.4 120 5.1 5.2 135 5.1 5.1 1505.2 4.9 165 5.3 4.9 180 5.3 4.8 195 5.4 4.8 210 5.4 5.2 225 5.6 5.2 2405.6 5.4

The results show that the oral insulin formulation of the presentinvention, at a dosage of three times higher than the injected level, iscomparable to the injected insulin.

Example 9

This example illustrates a method for making a mixed micellarformulation according to the present invention.

In a 250 mL capacity glass beaker was added 5 g sodium lauryl sulphate,5 g sodium salicylate and 2.5 g edetate. The beaker was placed on thehot plate with a magnetic stirrer. To this dry powder mixture was added100 mL distilled water and the mixture was stirred, using the magneticstir bar, at a medium speed until all the powder was dissolved. Thebuffer solution was stored in a clean glass bottle at room temperature(pH 6.5).

A micellar insulin solution was then prepared in a 50 mL capacity glassbeaker, into which was placed 11.54 mg insulin powder. To this powderwas added 10 mL of the buffer solution. The solution was continuouslystirred using a magnetic stir bar until all of the insulin powder wasdissolved and a clear solution obtained. The micellar solution so formedwas stored in clean glass bottles and refrigerated.

A 2% menthol solution was then prepared from 100 mg menthol crystals,dissolved in 5 mL ethanol. To this solution was added 5 mg FD & C bluedye. The solution was stirred for 10 minutes and stored in a glassbottle at room temperature.

Mixed micellar insulin was then prepared in a 50 mL glass beaker, inwhich was placed 100 mg of phosphatidylcholine (Sigma, type I=EH,hydrogenated). To this powder was added 10 mL of isopropyl alcohol. Themixture was stirred at a high speed (1000 rpm) for about minutes toensure complete dissolution of the phosphatidylcholine. To this solutionwas added the micellar insulin solution very slowly, drop wise, usingglass dropper, with continuous stirring at a high speed. The solutionwas stirred continuously for another 30 minutes at a high speed toensure uniform micellar particle size distribution. To this solution wasadded 1 mL of the 26 menthol solution and 50 mg sodium hyaluronate. Thesemi-clear, translucent, light blue colour, insulin mixed micellarsolution (final volume 15 mL) was stored in a clean glass bottle andrefrigerated. The solution had a pH of 6.5.

If the phosphatidylcholine powder does not dissolve completely, thenheating up to about 45° C. may be required, e.g. using a water bath.

It has been found that if the micellar insulin composition is not addedslowly, then the mixed micellar formulation will not be formed and theformulation will be gelatinous and sticky.

Example 10

The formulation of Example 9 was tested in a manner similar to thatindicated in Example 8 except that the formulation of the presentinvention was administered nasally.

On the first day, the ten volunteers each received 10 units insulininjection (regular fast acting, Eli Lilly). On the second day, thevolunteers received 20 units of the “oral” insulin of Example 9 (2 timesthe injection dose). The “oral” insulin was administered as drops (0.4mL volume per drop, approximately 4 large drops in total, i.e. two dropsin each nostril).

The results, showing the average for the, ten volunteers, were asfollows:

TABLE X Blood glucose levels (mmol/L) Time (minutes) Nasal Dose (20units) Injection (10 units) 0 7.4 6.8 15 6.7 7.0 30 5.9 6.8 45 5.3 6.360 5.0 6.3 75 5.2 5.8 90 5.1 5.2 105 5.0 5.0 120 4.6 5.2 135 4.5 4.2 1504.3 4.6 165 4.3 4.0 180 4.8 4.1 195 5.3 4.3 210 5.4 4.5 225 5.7 4.7 2405.6 5.0

The results show that the nasal insulin formulation of the presentinvention, at a dosage of twice the injected level, is comparable to theinjected insulin.

Example 11

The formula of Example 9 was taken and tests performed to determine theinsulin action on meal glucose on healthy volunteers.

Usually, diabetic patients take an insulin injection minutes prior to ameal, because injected insulin takes a long time to take effect.Injected insulin is slowly absorbed into bloodstream within 60 minutesand has metabolic effect on meal glucose levels.

The mixed micellar formulation of Example 9 was tested in healthyvolunteers under controlled conditions to determine the oral insulineffect on meal glucose when compared to injected insulin.

In one set of tests, ten healthy non-diabetic human volunteers weretested with insulin, by injection. In another set of tests thevolunteers were tested with insulin, taken orally. The volunteers fastedfrom midnight prior to the tests, with food being taken 30 minutes afterdosing. The meals were standard Sastacal 240 mL liquid diet approved bythe Diabetic Society, containing 400 calories.

On the first day, the volunteers received 10 units insulin by injection(regular fast acting insulin, available from Eli Lilly). On the secondday, the volunteers received 30 units of the above-prepared oral insulin(3 times the injection dose). In both tests, blood glucose levels weremonitored every 15 minutes by Bayer's Glucometer Elite. The results areshown on the following page:

TABLE XI Blood glucose levels (mmol/L) Time (minutes) Oral Dose (30units) Injection (10 units) 0 5.7 5.5 15 5.2 5.6 30 5.0 5.4 45 5.3 5.460 5.4 5.6 75 6.3 6.6 90 6.9 7.0 105 6.0 5.9 120 5.8 5.6 135 5.5 5.1 1505.1 4.8 165 4.9 4.6 180 4.8 4.3

The results indicate that the oral insulin helps to control meal glucoselevels in healthy volunteers when compared to injected insulin.

Example 12

The mixed micellar formulation of Example 9 was tested in diabeticvolunteers under controlled conditions to determine the oral insulineffect on meal glucose when compared to injected insulin.

In one set of tests, ten Type II diabetic human volunteers who tookinsulin, by injection three times a day, were studied. In another set oftests the volunteers were tested with insulin, taken orally. Thevolunteers fasted from midnight prior to the tests, with food beingtaken 30 minutes after dosing. The meals were standard Sastacal 240 mLliquid diet approved by the Diabetic Society, containing 400 calories.

On the first day, the volunteers received 10 units insulin by injection(regular fast acting insulin, available from Eli Lilly). On the secondday, the volunteers received 30 units of the above-prepared oral insulin(3 times the injection dose). In both tests, blood glucose levels weremonitored every 15 minutes by Bayer's Glucometer Elite.

The average results for the 10 volunteers were as follows:

TABLE XII Blood glucose levels (mmol/L) Time (minutes) Oral Dose (30units) Injection (10 units) 0 8.8 8.7 15 8.1 8.8 30 8.0 8.9 45 8.4 10.160 10.2 11.8 75 11.8 11.8 90 12.3 12.2 105 10.8 11.2 120 9.6 10.4 1358.1 8.4 150 6.9 7.3 165 6.2 6.5 180 4.8 4.3

The results indicate that oral insulin helps to control meal glucoselevels in diabetic patients when compared to injected insulin.

Example 13

A chewable gum insulin formulation was prepared by vigorously stirringthe insulin mixed micellar solution of Example 9 while adding guar gum,beeswax, powdered acacia, oleic acid, gamma-linoleic acid and sorbitol.For each 30 units of insulin, the mixture contained 100 mg guar gum, 50mg beeswax, 50 mg powdered acacia, 100 mg oleic acid, 100 mggamma-linoleic acid and 1 mL 3% sorbitol in ethanol solution. Themixture was then poured into a flat tray coated withpolytetrafluoroethylene until the mixture was about 10 mm deep. Themixture then solidified and after solidification was cut into sticksabout 1 cm by 3 cm. Each stick contained about 30 units insulin.

The mixed micellar formulation in chewable stick form was tested indiabetic volunteers under controlled conditions to determine the oralinsulin effect on meal glucose when compared to injected insulin.

In one set of tests, five Type II diabetic human volunteers who tookinsulin, by injection three times a day, were studied. In another set oftests the volunteers were tested with the chewable gum insulin, takenorally. The volunteers fasted from midnight prior to the tests, withfood being taken 30 minutes after dosing. The meals were standardSastacal 240 mL liquid diet approved by the Diabetic Society, containing400 calories.

On the first day, the volunteers received 10 units insulin by injection(regular fast acting insulin, available from Eli Lilly). On the secondday, the volunteers received 30 units of the above-prepared chewable gumoral insulin (3 times the injection dose), in both tests, blood glucoselevels were monitored every 15 minutes by Bayer's Glucometer Elite.

The average results for the five volunteers were as follows:

TABLE XIII Blood glucose levels (mmol/L) Time (minutes) Oral Dose (30units) Injection (10 units) 0 9.1 8.8 15 9.3 8.2 30 9.3 8.0 45 10.2 8.460 11.2 9.2 75 12.1 10.3 90 12.9 11.8 105 13.2 11.6 120 12.8 11.0 13512.2 10.2 150 11.6 9.6 165 11.0 9.5 180 10.6 9.1 195 10.0 8.7 210 9.58.2 225 8.8 8.0 240 8.2 7.5

Example 14

Another experiment, within the scope of the present invention, wasperformed, in this example, the formulation was for oral administration.

A buffer solution was prepared using 0.5 g sodium lauryl sulphate, 0.5 gsodium salicylate and 0.25 g disodium edetate dissolved in 10 mL ofwater. The solution was added to 8 mg (200 units) insulin and mixed, toform micellar insulin.

To this micellar solution were added 0.2 g bacitracin and 0.5 g eveningprimrose oil and the solution was mixed vigorously to form a mixedmicellar insulin solution (about 20 units/mL).

Six human volunteers were studied. The volunteers fasted from midnightprior to the test, with no food being taken during the 4 hour study.

On the first day, the volunteers received 10 units insulin by injection(regular fast acting insulin, available from Eli Lilly). On the secondday, the volunteers received 20 units of the above-prepared oral insulin(twice the injection dose). In both tests, blood glucose levels weremonitored at intervals by Bayer's Glucometer Elite.

The results, showing the average for the six volunteers, were asfollows:

TABLE XIV Blood glucose levels (mmol/L) Time (minutes) Oral Dose (20units) Injection (10 units) 0 8.8 7.9 15 8.4 7.9 30 8.1 8.2 45 7.4 8.360 6.3 7.6 90 5.1 6.2 120 5.0 5.2 150 4.8 4.6 180 5.1 3.9 210 5.3 4.4240 5.6 5.2

The results show that the oral insulin formulation of the presentinvention, at a dosage of twice the injected level, is comparable to theinjected insulin.

Example 15

A further experiment was performed to show another method of making themixed micellar formulation of the 15 present invention. In a 250 mLround bottom flask was added 100 mg of saturated lecithin powder(Phospholipon-90H) purchased from the American Lecithin Co. To thispowder was added 5 mL of absolute ethanol (USP grade). The flask wasthen attached to a rotary evaporator equipped with the vacuum pump andnitrogen inlet for inert atmosphere condition to minimize oxidation ofthe lecithin. The flask was rotated at 100-150 rpm under vacuum. Thesolution in the flask was heated to 60° C. by means of water bath todissolve the powder completely. After complete dissolution of thepowder, heating was stopped and the rotation speed was increased to 300rpm, under vacuum in nitrogen atmosphere until the alcohol evaporatedcompletely, leaving a uniform film on the side of the flask. Therotation was continued for at least 30 minutes to ensure uniform coatingof film on the wall and complete solvent removal. After 30 minutes therotation was stopped and the vacuum was released.

To this flask was added micellar insulin solution which had beenprepared from an aqueous solution of insulin, sodium lauryl sulphate,sodium salicylate and disodium edetate. The flask was shaken with thehelp of shaker plate. Shaking was continued for at least 30 minutes andthen the solution was sonicated with a high frequency sonicating probefor another 60 minutes in order to form small uniform mixed micelles.The mixed micelles so obtained were analyzed by Malvern Zeta (trademark) particle size distribution measurement equipment equipped with thelaser light scattering device. The mixed micelles particle sizedistribution obtained by this method was between 2 and 9 nm. To thissolution was added 1 mL of 2% menthol solution and 50 mg sodiumhyaluronate. The semi-clear, translucent, light blue colour solution(final volume 10 mL) was stored in a clean glass bottle andrefrigerated. The solution had a pH of 6.5.

Example 16

Another experiment, within the scope of the present invention, wasperformed.

A buffer solution was prepared using 0.5 g sodium lauryl sulphate, 0.5 gsodium salicylate and 0.25 g disodium edetate dissolved in 10 mL ofwater. The solution was added to 8 mg (200 units) insulin and mixed, toform micellar insulin.

To this micellar solution were added 0.5 g borage oil and the solutionwas mixed vigorously to form a mixed micellar insulin solution (about 20units/mL).

1-25. (canceled)
 26. An oral transmucosal pharmaceutical chewing gumcomposition, the composition comprising: a pharmaceutical agent, water,an alkali metal C8 to C22 alkyl sulphate in a concentration of from 1 to10 wt./wt. % of the total formulation, a pharmaceutically acceptableedetate in a concentration of from 1 to 10 wt./wt. % of the totalformulation, at least one alkali metal salicylate in a concentration offrom 1 to 10 wt./wt. % of the total formulation, and at least oneabsorption enhancing compound, said absorption enhancing compound beingselected from the group consisting of lecithin, hyaluronic acid,pharmaceutically acceptable salts of hyaluronic acid,octylphenoxypolyethoxyethanol, glycolic acid, lactic acid, chamomileextract, cucumber extract, oleic acid, linolenic acid, borage oil,evening primrose oil, menthol, trihydroxy oxo cholanylglycine andpharmaceutically acceptable salts of trihydroxy oxo cholanylglycine,glycerin, polyglycerin, lysine, polylysine, polidocanol alkyl ethers andanalogues of polidocanol alkyl ethers, triolein and mixtures thereof,wherein the amount of each absorption enhancing compound is present in aconcentration of from 1 to 10 wt./wt. % of the total formulation, andthe total concentration of absorption enhancing compounds are less than50 wt./wt. % of the formulation, and an effective amount of a chewinggum base.
 27. The composition of claim 26, wherein the pharmaceuticalagent is selected from the group consisting of insulin, heparin, lowmolecular weight heparin, hirulog, hirugen, huridine, interferons,interleukins, cytokines, mono and polyclonal antibodies,chemotherapeutic agents, vaccines, glycoproteins, bacterial toxoids,hormones, calcitonins, insulin like growth factors (IGF), glucagon likepeptides (GLP-1), large molecule antibiotics, protein based thrombolyticcompounds, platelet inhibitors, DNA, RNA, gene therapeutics antisenseoligonucleotides, steroids, hypnotics and pain killers.
 28. Thecomposition of claim 27, wherein the pharmaceutical agent is insulin.29. The composition of claim 26, wherein the chewing gum base comprisesat least one ingredient chosen from guar gum, powdered acacia,carrageenan, beeswax and xanthan gum.
 30. The composition of claim 26,in which one of the absorption enhancing compounds is lecithin.
 31. Thecomposition of claim 30, wherein the lecithin is selected from the groupconsisting of sphingomyelin, cephalin, lysolecithin and mixturesthereof.
 32. The composition of claim 26, wherein the alkali metal C8 toC22 alkyl sulphate is sodium lauryl sulphate.
 33. The composition ofclaim 26, wherein the alkali metal salicylate is sodium salicylate. 34.The composition of claim 26, comprising an absorption enhancing compoundselected from the group consisting of hyaluronic acid, pharmaceuticallyacceptable salts of hyaluronic acid and mixtures thereof, theconcentration such absorption enhancing compound being from about 1 toabout 5 wt./wt. %.
 35. The composition of claim 34, comprising sodiumhyaluronate.
 36. The composition of claim 26, comprising oleic acid. 37.The composition of claim 26, comprising gamma-linoleic acid.
 38. Thecomposition of claim 26, comprising menthol.
 39. The composition ofclaim 26, comprising phosphatidylcholine.
 40. The composition of claim26, comprising insulin, sodium lauryl sulphate, sodium salicylate, apharmaceutically acceptable edetate, sodium hyaluronate, oleic acid,gamma-linoleic acid, menthol and phosphatidylcholine.